Prevention of addiction in pain management

ABSTRACT

The present invention provides a composition for treating pain. The composition includes a pharmaceutically acceptable analgesic with addictive liability and a GABAergic agent, such as gamma vinyl GABA (GVG) or topiramate, which is effective in reducing or eliminating the addictive liability of the analgesic without interfering with its pain relieving properties.

[0001] The present application is a continuation-in-part of U.S. patentapplication Ser. No. 09/853,548 filed on May 14, 2001.

[0002] This invention was made with Government support under contractnumber DE-AC 02-98CH10886, awarded by the U.S. Department of Energy. TheGovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] This invention relates to the prevention of addiction. Morespecifically, the invention relates to the administration of a compoundto prevent addiction to analgesics often administered in painmanagement.

[0004] For many years, the treatment of postoperative pain and thoseconditions associated with chronic pain have been one of the mosttroubling and difficult areas of medicine. In general treatment has beenso poor that laws have been enacted to ensure a patient's right toadequate pain management.

[0005] A major issue in pain management comes from the inability toquantify the adequacy of a pain control regimen. The clinical issues arecomplex, but it is clear that inadequate pain control leads to excessivemorbidity and poor clinical outcomes.

[0006] It has long been known that exact pain control will improve theclinical outcome and be associated with little or no addictionliability. In a typical clinical situation, however, exact pain controlis almost impossible to attain because pain generally fluctuates inintensity and rarely remains constant over time. On the other hand,treatment with opiates in excess of that required to control the painoften leads to chronic drug addiction and its unfortunate clinical andsocial consequences. See B. Meier and M. Petersen, “MedicineMerchants/Uses and Abuses: Use of Painkiller Grows Quickly, Along WithWide Spread Abuse,” New York Times, Mar. 5, 2001 at A1.

[0007] In general, physicians have chosen to under treat pain because oftheir legitimate concern that the risk of generating a person who willbe addicted to opiates long after the medical condition requiring opiatetreatment had resolved.

[0008] Thus, there is a need to be able to administer effective, butaddictive, analgesics without the unwanted side affect of developing anaddiction to such analgesics.

SUMMARY OF THE PRESENT INVENTION

[0009] The present invention provides a composition for treating pain ina mammal. The composition includes a pharmaceutically acceptableanalgesic having an addictive liability and a GABAergic agent effectivein reducing or eliminating the addictive liability of the analgesic. Ina preferred embodiment, the analgesic is a narcotic analgesic.

[0010] The GABAergic agent can be any agent that potentiates theGABAergic system or increased extra cellular and endogenous GABA levelsin the central nervous system. Preferred GABAergic agents include Gammavinyl GABA (GVG), gabapentin, valproic acid, progabide,gamma-hydroxybutyric acid, fengabine, cetylGABA, Topiramate, tiagabine,and acamprosate (homo-calcium-acetyltaurine). The GABAergic agent canalso include pharmaceutically acceptable salts of the GABAergic agent,an enantiomer or racemic mixture of the GABAergic agent, or anycombinations of the forgoing. GVG is most preferred.

[0011] In a preferred embodiment, the addictive liability includesdevelopment of dependency or development of tolerance for the analgesic.

[0012] A method is also provided for reducing or eliminating theaddictive liability of an analgesic in a host. The method includesadministering an analgesic having an addictive liability to a host andalso administering to said host a GABAergic agent effective in reducingor eliminating the addictive liability of the analgesic. It is preferredthat the GABAergic agent be administered contemporaneously with theanalgesic. The GABAergic agent can be administered before, after, orsimultaneously, with the analgesic, or any combination thereof. In apreferred embodiment, the analgesic and GABAergic agent are administeredsimultaneously in a single composition.

[0013] In a separate preferred embodiment, the reduction or eliminationof the addictive liability of the analgesic occurs in the absence of anaversive or appetitive response to the GABAergic agent. In a separatepreferred embodiment, the reduction or elimination of the addictiveliability is measured by conditioned place preference (CPP).

[0014] The analgesic can be any analgesic. An analgesic with anaddictive liability, for example, a narcotic analgesic, is preferred.Examples of narcotic analgesics include alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, desomorphine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, OxyContin®, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations.

[0015] Preferred GABAergic agents include Gamma vinyl GABA (GVG),gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid,fengabine, cetylGABA, topiramate, tiagabine, acamprosate(homo-calcium-acetyltaurine), pharmaceutically acceptable salts thereof,enantiomers or a racemic mixture thereof, or any combinations thereof.GVG is most preferred.

[0016] In the method of the invention, the host will generally bemammalian. A human host is most preferred.

[0017] The preferred amounts of GABAergic agents will vary. For example,in humans, it is preferred that GVG be administered in an amount ofabout 500 mg/day to about 6 g/day. It is preferred that gabapentin beadministered to humans in an amount of about 600 mg/day to about 3600mg/day. It is preferred that valproic acid be administered to humans inan amount of about 500 mg/day to about 2500 mg/day. It is preferred thattopiramate be administered to humans in an amount of about 100 mg/day toabout 1000 mg/day. It is preferred that progabide be administered tohumans in an amount of about 1000 mg/day to about 3000 mg/day. It ispreferred that fengabine be administered to humans in an amount of about700 mg/day to about 4000 mg/day. It is preferred thatgamma-hydroxybutyric acid be administered in an amount of about 1000mg/day to about 5000 mg/day.

[0018] The composition of the invention reduces or eliminates theaddictive liability of analgesics without interfering with thetherapeutic analgesic effects. This activity of the composition has theconsequence of increasing the therapeutic index of the analgesic agentby reducing or eliminating addiction as a major source of post treatmentmorbidity. Thus, the composition enables full and continuing paincontrol with less concern for generating post treatment drug addicts andabusers.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019]FIG. 1 is a graph illustrating the effect of GVG onmorphine-induced DA release in the nucleus accumbens (NAcc).

DETAILED DESCRIPTION OF THE INVENTION

[0020] The composition of the invention includes an analgesic compoundsuitable for use in reducing pain and a GABAergic agent effective inreducing or eliminating the addictive liability of the analgesic. Byadministering the compounds together in one composition, the compositionof the invention reduces or eliminates the addictive liability of thecompound administered to treat pain.

[0021] Analgesics are very often administered in the treatment of postoperative pain, both surgical and orthopedic. This pain is usuallycharacterized by fluctuating but gradually diminishing intensity over aperiod of days to weeks and months and requires ongoing pain management.Analgesics are also often utilized in the treatment of chronic painconditions, such as chronic back pain and sciatica and other neuralgias

[0022] The analgesic compound can be any pharmaceutically acceptableanalgesic for the treatment of pain, as is known in the art.Combinations of analgesics can also be used. However, the benefits ofthe compound are most realized when the analgesic agent possesses anaddictive liability.

[0023] Analgesics that possess an addictive liability are defined hereinas those analgesics that are recognized to develop physical and/orpsychological dependency following a single administration or repeatedadministrations for a short or prolonged period of time, and/orsubstantially develop tolerance to analgesic action thereof by repeatedadministrations for a short or prolonged period of time.

[0024] Examples of such analgesics include narcotic analgesics. Narcoticanalgesics are conventionally used in treating pain. Narcotic analgesicsinclude, for example, opioid analgesics such as alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,OxyContin®, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propiram, propoxyphene,sufentanil, tramadol, tilidine, salts thereof, mixtures of any of theforegoing, mixed mu-agonists/antagonists, mu-antagonist combinations,and the like.

[0025] Examples also include analgesic peptides as endogenousmorphine-like substances such as, for example, enkephalins such asmethionine enkephalin and leucine enkephalin; endorphins such as alpha-endorphin, beta -endorphin, and gamma -endorphin; and dynorphins suchas dynorphin A and dynorphin B, and precursors thereof whose examplesinclude proenkephalins such as proenkephalins, propiomelanocortins, andprodynorphins.

[0026] The analgesics are not limited to any physical form. Theanalgesic can be, for example, a solid or liquid. Two examples of liquidform analgesics are codeine syrups and Brompton's cocktail.

[0027] The composition of the present invention can further include oneor more additional drugs which may or may not act synergistically withthe analgesics utilized in the present invention. Examples of suchadditional drugs include non-steroidal anti-inflammatory agents,including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen,oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Other suitable additional drugswhich may be included in the dosage forms of the present inventioninclude acetaminophen, aspirin, and other non-opioid analgesics.

[0028] GABAergic agents as defined herein are agents that potentiate theGABAergic system or increase extracellular endogenous GABA levels in thecentral nervous system (CNS). Such compositions or medicaments includeagents that enhance the production or release of GABA in the CNS. Asused herein, enhancing or increasing endogenous CNS GABA levels isdefined as increasing or up-regulating GABA levels substantially overnormal levels in vivo, within a mammal. Preferably, endogenous CNS GABAlevels are enhanced at least by from about 10% to about 1000% overnormal levels.

[0029] GABAergic agents include, but are not limited to, Gamma vinylGABA (GVG), gabapentin, valproic acid, progabide, gamma-hydroxybutyricacid, fengabine, cetylGABA, Topiramate, tiagabine, and acamprosate(homo-calcium-acetyltaurine). The GABAergic agents can also includepharmaceutically acceptable salts of the GABAergic agent and enantiomeror a racemic mixtures of the GABAergic agent, or any combinations of theforegoing.

[0030] Different enantiomers may be synthesized from chiral startingmaterials, or the racemates may be resolved by conventional procedureswhich are well known in the art of chemistry; such as chiralchromatography, fractional crystallization of diastereomeric salts, andthe like.

[0031] Gabapentin is available as Neurontin® from Parke-Davis in theUnited States. Valproic acid is available as Depakene® and Depakote®from Abbott in the United States. Progabide is available as Gabrene®from Synthelabo, France. The chemical formula of progabide isC₁₇H₁₆N₂O₂. Fengabine is available as SL 79229 from Synthelabo, France.The chemical formula of fengabine is C₁₇H₇C₁₂NO. Gamma-hydroxybutyricacid is available from Sigma Chemical. The chemical formula ofgamma-hydroxybutyric acid is C₄H₇O₃Na. Topiramate is asulfamate-substituted monosaccharide of the formula C₁₂H₂₁NO₈S and isavailable commercially as Topomax® from McNeil in the United States.

[0032] GABAergic agents also embrace compositions or medicaments whichinclude prodrugs of GABA or drugs which contain GABA as a moiety in itschemical structure. The prodrugs become pharmacologically active whenmetabolically, enzymatically or non-enzymatically biotransformed orcleaved into GABA in the CNS. An example of a prodrug of GABA isprogabide which, upon crossing the blood brain barrier, increasesendogenous CNS GABA levels.

[0033] Gamma vinyl GABA (GVG) is a selective and irreversible inhibitorof GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition.GVG is C₆H₁₁, NO₂ or 4-amino-5-hexanoic acid available as VIGABATRIN®from Hoechst Marion Roussel. GVG does not bind to any receptor orreuptake complex, but increases endogenous intracellular GABA levels byselectively and irreversibly inhibiting GABA-transaminase (GABA-T), theenzyme that normally catabolizes GABA.

[0034] As used herein GVG includes the racemic compound or mixture whichcontains equal amounts of S(+)-gamma-vinyl GABA, and R(−)-gamma vinylGABA. This racemic compound of GVG is available as SABRIL® from AventisPharma AG.

[0035] GVG contains asymmetric carbon atoms and thus is capable ofexisting as enantiomers. The present invention embraces any enantiomericform of GVG including the racemates or racemic mixture of GVG. In somecases there may be advantages, i.e. greater efficacy, to using aparticular enantiomer when compared to the other enantiomer or theracemate or racemic mixture in the methods of the instant invention andsuch advantages can be readily determined by those skilled in the art.For example, the enantiomer S(+)-gamma-vinyl GABA is more effective atincreasing endogenous intracellular GABA levels than the enantiomerR(−)-gamma-vinyl GABA.

[0036] As used herein, pharmaceutically acceptable salts include thosesalt-forming acids and bases which do not substantially increase thetoxicity of the compound. Some examples of suitable salts include saltsof mineral acids such as hydrochloric, hydriodic, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, as well as saltsof organic acids such as tartaric, acetic, citric, malic, benzoic,glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g.p-toluenesulfonic acids, and the like.

[0037] All modes of administration are contemplated for the compositionof this invention. Systemic modes of administration, such as oral andparenteral are preferred. The administration of the composition of theinvention can also include controlled-release delivery systems, as isknown in the art.

[0038] The composition will ordinarily be formulated with one or morepharmaceutically acceptable ingredients in accordance with known andestablished practice. Thus, the composition can be formulated, forexample, as a liquid, powder, elixir, injectable solution or suspension,etc. Formulations for oral use can be provided as tablets, caplets orhard capsules wherein the pharmacologically active ingredients are mixedwith an inert solid diluent such as calcium carbonate, calcium phosphateor kaolin, or as soft gelatin capsules wherein the active ingredientsare mixed with an oleaginous medium, e.g., liquid paraffin or olive oil.

[0039] Examples of the pharmaceutical compositions suitable forparenteral administration include, for example, injections forsubcutaneous, intravenous, and intramuscular injections, drip infusions,suppositories, inhalants, transdermal preparations, transmucosalpreparations, and patches. Examples of the pharmacologically andpharmaceutically acceptable additives include, for example, excipients,disintegrators or disintegrating aids, binders, lubricants, coatingagents, coloring agents, diluents, base materials, solubilizers orsolubilizing aids, isotonicities, pH modifiers, stabilizers,propellants, and adhesives.

[0040] Aqueous suspensions can include pharmaceutically acceptableexcipients such as suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as naturally occurring phosphatide,e.g., lecithin, or condensation products of an alkylene oxide with fattyacids, e.g., polyoxyethylene stearate, or condensation products ofethylene oxide with long chain aliphatic alcohols, e.g,heptadecaethylene-oxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, e.g.,polyoxyethylene sorbitol monoleate or condensation products of ethyleneoxide with partial esters derived from fatty acids and hexitolanhydrides, e.g., polyoxyethylene sorbitan monoleate. The aqueoussuspensions can also contain one or more preservatives, e.g.,ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, saccharin or sodium or calcium cyclamate.

[0041] For intranasal administration, the compounds of the invention canbe used, for example, as a liquid spray, as a powder or in the form ofdrops. For administration by inhalation, the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit can be determined by providing avalve to deliver a metered amount. Capsules and cartridges of, forexample, gelatin, for use in an inhaler or insulator can be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

[0042] The dose of the analgesic is that amount effective to preventoccurrence of the symptoms of pain or to treat some symptoms of painfrom which the host suffers, as is known in the art. The amount of theanalgesic in the composition may suitably be chosen depending on, forexample, administration route, degree of the development of dependencyand/or the development of tolerance, purpose of administration such asprophylactic or therapeutic administration, and the age or body weightof a patient. Also, because the composition of the invention iseffective in inhibiting or eliminating the addictive liability of theanalgesic, higher doses of the analgesic may be administered to thehost.

[0043] By “effective amount” of analgesic, it is meant that amountsufficient to elicit the desired pharmacological or therapeutic effects,thus resulting in effective prevention or treatment of pain. Preventionof pain is manifested by prolonging or delaying the onset of pain.Treatment of pain is manifested by a reduction in the symptoms of painassociated with pain or amelioration of the re-occurrence of thesymptoms of pain. The specific amount of analgesic in the composition ofthe invention will vary depending upon, among other things, theindividual to be treated, the source and severity of the pain, and thespecific type of analgesic administered, as is known in the art. Inhumans, for example, an effective amount can vary from about 5 μg toabout 1000 mg, preferably from about 50 μg to about 100 mg.

[0044] The amount of GABAergic agent in the composition of the inventionis that amount effective in reducing or eliminating the addictiveliability of the analgesic. It is preferred that the GABAergic agentalso be administered in an amount that minimizes any potential sideeffects in the host. The effective amount will vary depending upon thedose of analgesic administered. The amount of GABAergic agent can varydue to additional factors, for example, on administration route, theaddictive liability of the analgesic, the tolerance of the host to theanalgesic, and age or body weight. In a preferred embodiment, theGABAergic agent will also have little or no effect on the therapeuticeffects of the analgesic. In humans, for example, the preferred amountof GABAergic agent in the composition is about 0.5 to about 5 grams.

[0045] As to examples of the dose, where the composition of theinvention includes a narcotic analgesic agent, such as morphinehydrochloride or morphine nitrate, in an amount from about 10 to 30 mg,the composition of the invention can typically include between about 25to about 1000 mg, preferably from about 100 to about 500 mg of GABAergicagent, such as GVG.

[0046] The host or patient for the analgesic therapeutic treatment usingthe analgesic compounds described herein generally is mammalian. Mammalsinclude, for example, humans, baboons and other primates, as well as petanimals such as dogs and cats, laboratory animals such as rats and mice,and farm animals such as horses, sheep, and cows.

[0047] Without being bound by theory, it is believed that the addictiveliability of narcotic analgesics is linked to its pharmacologicalactions on mesotelencephalic dopamine (DA) reinforcement/reward pathwaysin the central nervous system (CNS). Dopaminergic transmission withinthese pathways is modulated by gamma-amino butyric acid (GABA).

[0048] It has been found that addicting drugs such as morphine and otheranalgesic drugs used in the treatment of pain enhance dopamine (DA)within the mesotelencephalic reward/reinforcement circuitry of theforebrain, producing the enhanced brain reward that constitutes the druguser's “high.” Alterations in the functions of the dopamine (DA) systemshave also been implicated in drug craving and in relapse to thedrug-taking habit in recovering addicts. For example, morphine acts onthese DA systems by binding to the dopamine transporter (DAT) andpreventing DA reuptake into the presynaptic terminal. There isconsiderable evidence that the addictive liability of addicting drugs islinked to the reuptake blockade in central nervous system (CNS)reward/reinforcement pathways.

[0049] It is believed that narcotic analgesics inhibit the presynapticreuptake of monoamines. Dopaminergic neurons of the mesocorticolimbic DAsystem, whose cell bodies lie within the ventral tegmental area (VTA)and project primarily to the nucleus accumbens (NAcc), appear to beinvolved in narcotic reinforcement. Electrical stimulation of rewardcenters within the VTA increases extracellular DA levels in the NAcc,while 6-hydroxy dopamine lesions of the NAcc abolish self-administrationof addicting drugs. In vivo microdialysis studies confirm morphine'sability to increase extracellular DA in the NAcc.

[0050] γ-Amino butyric acid (GABA)ergic neurons in the NAcc and ventralpallidum project onto DA neurons in the VTA. Pharmacologic andelectrophysiologic studies indicate these projections are inhibitory.Inhibition of VTA-DA neurons is likely the result of GABAB receptorstimulation. In addition, microinjection of baclofen into the VTA,acting via these receptor subtypes, can decrease DA concentrations inthe NAcc. Taken together, it is evident that pharmacologic manipulationof GABA may effect DA levels in the NAcc through modulation of VTA-DAneurons.

[0051] Based on the knowledge that narcotic analgesics increaseextracellular NAcc DA and the fact that GABA inhibits DA in the samenuclei, the inventors have shown that GABAergic agents can attenuatenarcotic analgesic-induced changes in extracellular DA. For example, GVGsignificantly attenuated morphine-induced DA increases in the nucleusaccumbens in rats (NAcc). See Example 1.

[0052] Therefore, the inventors have developed the utility of apharmacologic strategy targeted at the GABAergic neurotransmittersystem, a system distinct from but functionally linked to the DAmesotelencephalic reward/reinforcement system, in avoiding the addictiveliability in administering analgesics for treatment of pain. However,rather than targeting the GABA receptor complex with a direct GABAagonist, this novel approach with GABAergic agents takes advantage ofthe prolonged effects of an irreversible enzyme inhibitor that raisesendogenous GABA levels without the addictive liability associated withGABA agonists acting directly at the receptor itself. Thus, theGABAergic agent can eliminate the addiction liability of the analgesicby interfering with the process that produces craving and reward withoutinterfering with the ability of the analgesic to reduce pain in thehost.

[0053] Accordingly, a method is provided for reducing or eliminating theaddictive liability of an analgesic as defined above in a host. Themethod includes administering the analgesic to the host andadministering an effective amount of a GABAergic agent.

[0054] As discussed above, the analgesic can be any pharmaceuticallyacceptable analgesic for the treatment of pain, as is known in the art,including combinations of analgesics. In a preferred embodiment, theanalgesics possess an addictive liability. The analgesics also are notlimited to any physical form. The analgesic can be, for example, a solidor liquid. Two examples of liquid form analgesics are codeine syrups andBrompton's cocktail.

[0055] As discussed above, analgesics that possess an addictiveliability are defined herein as those analgesics that are recognized todevelop dependency characteristics by a single administration orrepeated administrations for a short or prolonged period of time, and/orsubstantially develop tolerance to analgesic action thereof by repeatedadministrations for a short or prolonged period of time.

[0056] An effective amount of GAB Aergic agent, as defined herein, isthat amount effective in reducing or eliminating the addictive liabilityof the analgesic. It is preferred that the GABAergic agent also beadministered in an amount that minimizes any potential side effects inthe host. The effective amount will vary depending upon the dose ofanalgesic administered. The amount of GABAergic agent can vary due toadditional factors, for example, the administration route, the addictiveliability of the analgesic, the tolerance of the host to the analgesic,and age or body weight. In a preferred embodiment, the GABAergic agentwill also have little or no effect on the therapeutic effects of theanalgesic.

[0057] The effective amount of GABAergic agent should be sufficient toincrease endogenous CNS GABA levels. As used herein, increasingendogenous CNS GABA levels is defined as increasing or up-regulatingGABA levels substantially over normal levels in vivo, within a mammal.Preferably, endogenous CNS GABA levels are enhanced at least by fromabout 10% to about 1000% over normal levels.

[0058] Examples of an effective amount of GVG in mammals include anamount from about 10 mg/kg/day to about 100 mg/kg/day, preferably fromabout 25 mg/kg/day to about 80 mg/kg/day. In humans, the preferred rangeis from about 500 mg/day to about 6 g/day, more preferably from 1 g/dayto 4 g/day.

[0059] Examples of an effective amount of gabapentin in mammals includean amount from about 10 mg/kg/day to about 40 mg/kg/day, preferably fromabout 15 mg/kg/day to about 30 mg/kg/day. In humans, the preferred rangeis from about 600 mg/day to about 3600 mg/day, more preferably from 900mg/day to 2400 mg/day. Gabapentin is available as NEURONTIN® fromParke-Davis in the United States.

[0060] Examples of an effective amount of valproic acid in mammalsinclude an amount from about 10 mg/kg/day to about 60 mg/kg/day,preferably from about 15 mg/kg/day to about 30 mg/kg/day. In humans, thepreferred range is from about 500 mg/day to about 2500 mg/day, morepreferably from 750 mg/day to 1750 mg/day. Valproic acid is available asDEPAKENE® and DEPAKOTE® from Abbott in the United States.

[0061] Examples of an effective amount of topiramate in mammals includean amount from about 5 mg/kg/day to about 80 mg/kg/day, preferably from5 mg/kg/day to about 15 mg/kg/day. In humans, the preferred range isfrom about 100 mg/day to about 1000 mg/day, more preferably from 200mg/day to 600 mg/day. Topiramate is available as TOPAMAX® from McNeil inthe United States.

[0062] Examples of an effective amount of progabide in mammals includean amount from about 5 mg/kg/day to about 75 mg/kg/day, preferably from15 mg/kg/day to about 45 mg/kg/day. In humans, the preferred range isfrom about 1000 mg/day to about 3000 mg/day, more preferably from 1500mg/day to 2500 mg/day. Progabide is available as GABRENE® fromSynthelabo, France. The chemical formula of progabide is C₁₇H₁₆N₂O₂.

[0063] Examples of an effective amount of fengabine in mammals includean amount from about 5 mg/kg/day to about 80 mg/kg/day, preferably from15 mg/kg/day to about 50 mg/kg/day. In humans, the preferred range isfrom about 700 mg/day to about 4000 mg/day, more preferably from 1000mg/day to 3000 mg/day. Fengabine is available as SL 79229 fromSynthelabo, France. The chemical formula of fengabine is C₁₇H₁₇C₁₂NO.

[0064] Examples of an effective amount of gamma-hydroxybutyric acid inmammals include an amount from about 5 mg/kg/day to about 100 mg/kg/day,preferably from 10 mg/kg/day to about 80 mg/kg/day. In humans, thepreferred range is from about 700 mg/day to about 5000 mg/day, morepreferably from 1000 mg/day to 4000 mg/day. Gamma-hydroxybutyric acid asthe sodium salt is available from Sigma Chemical.

[0065] Compulsive drug use includes three independent components:tolerance, psychological dependence, and physical dependence. Toleranceproduces a need to increase the dose of the drug after it is usedseveral times in order to achieve the same magnitude of effect. Physicaldependence is an adaptive state produced by repeated drug administrationand which manifests itself by intense physical disturbance when drugadministration is halted. Psychological dependence is a conditioncharacterized by an intense drive, craving or use for a drug whoseeffects the user feels are necessary for a sense of well being. SeeFeldman, R. S. and Quenzer, L. F. “Fundamentals ofNeuropsychopharmocology” 418-422 (Sinaur Associates, Inc.) (1984)incorporated herein by reference as if set forth in full. Based on theforegoing definitions, as used herein “dependency characteristics”include all characteristics associated with compulsive drug use,characteristics that can be affected by biochemical composition of thehost, physical and psychological properties of the host.

[0066] Rewarding/incentive effects refers to any analgesic stimulus thatproduces anhedonia or increases the probability of a learned response.This is synonymous with reinforcement. With respect to experimentalanimals, a stimulus is deemed to be rewarding by using paradigms thatare believed to measure reward. This can be accomplished by measuringwhether stimuli produce an approach response, also known as anappetitive response or a withdrawal response, as when the animal avoidsthe stimuli, also known as an aversive response. Conditioned placepreference (CPP) is a paradigm which measures approach (appetitive) orwithdrawal (aversive) responses. One can infer that rewarding stimuliproduce approach behavior. In fact, one definition of reward is anystimulus that elicits approach behavior. Furthermore, the consequencesof reward would be to enhance the incentive properties of stimuliassociated with the reward.

[0067] Reward can also be measured by determining whether the deliveryof a reward is contingent upon a particular response, thereby increasingthe probability that the response will reappear in a similar situation,i.e. reinforcement paradigm. For example, a rat pressing a bar a certainnumber of times for an injection of a drug is an example ofreinforcement. Yet another way to measure reward is by determining if astimulus (e.g. a drug), through multiple pairings with neutralenvironmental stimuli, can cause the previously neutral environmentalstimuli to elicit behavioral effects initially only associated with thedrug. This is conditioned reinforcement. CPP is considered to be a formof conditioned reinforcement.

[0068] The incentive motivational value of a drug can be assessed usingconditioned place preference (CPP). Animals are tested in a drug-freestate to determine whether they prefer an environment in which theypreviously received the drug as compared to an environment in which theypreviously received saline. In the CPP paradigm, animals are given thedrug in one distinct environment and are given the appropriate vehiclein an alternative environment. The CPP paradigm is widely used toevaluate the incentive motivational effects of drugs in laboratoryanimals. After conditioning or pairing with the drug, if the animal, ina drug-free state, consistently chooses the environment previouslyassociated with the drug; the inference is drawn that the appetitivevalue of the drug was encoded in the brain and is accessible in thedrug-free state. CPP is reflected in an increased duration spent in thepresence of the drug-associated stimuli relative to vehicle-injectedcontrol animals.

[0069] It has been postulated that since craving at the human level isoften elicited by sensory stimuli previously associated withdrug-taking, conditioning paradigms like CPP may be used to modelcraving in laboratory animals.

[0070] As used herein, craving an analgesic is a desire toself-administer the analgesic previously used by the mammal. The mammaldoes not necessarily need the analgesic to prevent withdrawal symptoms.

[0071] As discussed above, any form of administration is contemplated inthe method of the invention. The GABAergic agent can be administeredbefore, during, or simultaneous with the analgesic, or any combinationthereof. Simultaneous administration is preferred. If the administrationof GABAergic agent and analgesic is simultaneous, the composition of theinvention as described above can be utilized.

[0072] Systemic administration by the parenteral and enteral routes ispreferred. For example, the GABAergic agents can be administeredintravenously, or intraperitoneal (i.p.).

[0073] Oral or enteral use in also contemplated. Formulations such astablets, capsules, pills, troches, elixirs, suspensions, syrups, wafers,chewing gum and the like can be employed to provide the GABAergic agent.

[0074] The following examples are provided to assist in a furtherunderstanding of the invention. The particular materials and conditionsemployed are intended to be further illustrative of the invention andare not limiting upon the reasonable scope thereof.

EXAMPLE 1

[0075] The effects of increased endogenous GABA activity onmorphine-induced extracellular DA concentrations in the nucleusaccumbens (NAcc) of freely moving rats was explored.

[0076] All animals were used under an IACUC-approved protocol and withstrict adherence to the NIH guidelines. Adult male Sprague-Dawley rats(200-300 g, Taconic Farms), housed in the animals care facility under12:12 light/dark conditions, were placed into 6 groups (n=3-6),anesthetized and siliconized guide cannulae were stereotacticallyimplanted into the right NAcc (2.0 mm anterior and 1.0 mm lateral tobregms, and 7.0 mm ventral to the cortical surface) and prefrontalcortex (PFC) at least 4 days prior to study. Microdialysis probes (2.0mm, Bioanalytical Systems, BAS, West Lafayette, Ind.) were positionedwithin the guide cannulae and artificial cerebrospinal fluid (ACSF,155.0 mM NA⁻, 1.1 mM Ca²⁻, 2.9 mM K⁻, 132.76 mM C1⁻, and 0.83 mM Mg²⁻)was administered through the probe using a CMA/100 microinfusion pump(BAS) at a flow rate of 2.0 μl/min.

[0077] Animals were placed in bowls, and probes were inserted andflushed with ACSF overnight. On the day of the study, a minimum of threesamples were injected to determine baseline stability. Samples werecollected for 20 min. and injected on-line (CMA/160, BAS). The averagedopamine concentration of these three stable samples was defined ascontrol (100%), and all subsequent treatment values were transformed toa percentage of that control. Upon establishing a stable baseline, themorphine was administered by intraperitoneal (i.p.) injection. The highperformance liquid chromatography (HPLC) system consists of a BASreverse-phase column (3.0μ C-18), a BAS LC-4C electrochemical transducerwith a dual/glassy carbon electrode set at 650 mV, a computer thatanalyzes data on-line using a commercial software package (ChromographBioanalytical Systems), and a dual pen chart recorder. The mobile phase(flow rate 1.0 ml/min) consisted of 7.0% methanol, 50 mM sodiumphosphate monobasic, 1.0 mM sodium octyl sulfate, and 0.1 mm EDNA, pH4.0. DA eluted at 7.5 min.

[0078] Gamma-vinyl GABA (GVG), an irreversible inhibitor ofGABA-transaminase, was administered by intraperitoneal injection 2.5hours prior to morphine (7 mg/kg). In all studies, animals were placedin the microdialysis bowls the night before the experiment andartificial cerebrospinal fluid (ACSF) was perfused through themicrodialysis probes at a flow rate of 2.0 μl/min. At the end of eachstudy, animals were sacrificed and their brains were removed andsectioned for probe placement verification.

[0079] Levels of extracellular DA were sampled from the NAcccontinuously using a stereoaxically implanted probe. The results areshown in FIG. 2. Morphine alone increases DA concentrations 50% abovebaseline in the NAcc (p<0.01, T=3.79). GVG dose dependently diminishedthe DA response to morphine in the NAcc, with no significant inhibitionafter 150 mg/kg, 62% attenuation following 300 mg/kg (p<0.01, T =4.97)and 67% attenuation following 500 mg/kg (p<0.001, T =6.02). This dataindicates the GABAergic system as a target for reducing or eliminatinganalgesic addictive liability by reducing extracellular DAconcentrations.

EXAMPLE 2

[0080] The effect of GVG on the analgesic potency of morphine in maleSprague-Dawley rats was examined using the hot plate test. In thisparadigm, animals are treated and placed on a hot plate at a temperatureof 53 degrees Centigrade and the latency to licking of one of theforepaws was measured. This test is used as screen for agents that havemoderate to significant analgesic action as these drugs will increaselatency to forepaw licking.

[0081] The rats were treated with either vehicle or GVG 2.5 hours priorto receiving either vehicle or morphine. Animals were given eithervehicle or morphine 30 minutes prior to placing them on a hot plate at aconstant temperature of 53 degrees Centigrade. Analgesic potency wasassessed by measuring the latency to forepaw licking after placement onthe hot plate. A total of 10 rats were examined for each treatmentgroup. Each value represents the latency in seconds to forepaw licking ±S.E.M. The results are set forth in Table 1. TABLE 1 PretreatmentTreatment Licking latency (sec) Vehicle, 1 ml/kg Vehicle, 1 ml/kg 11 ±0.8 GVG, 300 mg/kg Vehicle, 1 ml/kg 17 ± 1.4+ Vehicle, 1 ml/kg Morphine,10 mg/kg 27 ± 3.0* GVG, 300 mg/kg Morphine, 10 mg/kg 27 ± 2.9#

[0082] The results clearly indicate that 10 mg/kg i.p. of morphineproduces a significant increase in the latency to forepaw lickingcompared to vehicle-treated animals, i.e. morphine produces an analgesiceffect. In addition, GVG +vehicle produced a significantly greaterlatency than vehicle +vehicle. However, the administration of GVG 2.5hrs prior to morphine did not significantly alter the latency to forepawlicking compared to vehicle +morphine. These results indicate that 300mg/kg i.p of GVG, does not alter the analgesic potency of morphine.

EXAMPLE 3

[0083] Heroin-induced conditioned place preference was then examined.Heroin is an effective analgesic, similar to morphine.

[0084] In all rodent studies, male Sprague-Dawley rats were used(200-225 g, Taconic farms, Germantown, N.Y.). Animals were allowed toacclimate to the animal housing facility for at least 5 days prior tobeginning the experiments. Conditioned place preference (CPP) chamberswere used as previously described (Lepore et al., 1995), except insteadof one chamber being entirely white and the other black, one chamber wasentirely light blue with a stainless steel floor and the second chamberwas light blue with horizontal black stripes (2.5 cm wide) spaced 3.8 cmapart with a smooth plexiglass floor. In all CPP studies with GVG, thesaline volume was (1 ml/kg), and the heroin doses were 1.5 mg/kg. Thesaline, heroin and GVG were all injected intraperitonealy (i.p.). Theconditioning procedure for the acquisition phase consisted of 12sessions carried out consecutively over 12 days.

[0085] The CPP pairings were: 1) saline/saline 2) saline/heroin 3)GVG/saline 4) saline/heroin and GVG. The animals in each group wererandomly assigned to a 2×2 factorial design with one factor being thepairing chamber and the other factor being the order of conditioning.The animals that received either saline or heroin were injected andconfined to the appropriate compartment for 30 minutes. The GVGinjections were given 3 hours before saline or heroin injection andsubsequent placement of the animals in the appropriate chamber. This wasdone as it has been shown that GABA levels reach maximal values 3 to 4hours following GVG administration.

[0086] On the test day (day 12), neither drugs nor saline wereadministered and the animal was allowed to move freely between bothchambers for fifteen minutes. The amount of time spent in each chamberwas recorded using an automated infrared beam electronically coupled toa timer. For the expression phase of CPP to heroin, the animals werehabituated and conditioned to heroin as described in the acquisitionstudies, but no animals in the expression studies were given GVG onconditioning days. On the test day (day 12), the animals being tested inthe expression phase, unlike the animals in the acquisition phase,received either saline or GVG 2.5 hours before they were placed in theapparatus and allowed free access to both chambers for 15 minutes.

[0087] The results are set forth in Table 2 below. TABLE 2 TreatmentPairings Drug given on test Time spent in chambers (min) Paired/Unpairedday Paired Unpaired Vehicle/Vehicle Vehicle²  7.4 ± 0.4¹ 7.6 ± 0.4Vehicle/Heroin Vehicle 10.9 ± 0.4* 4.1 ± 0.4^(#) Vehicle/Heroin GVG, 300mg/kg  6.6 ± 0.7 8.4 ± 0.7 Vehicle/Vehicle GVG, 300 mg/kg  7.4 ± 0.3 7.6± 0.3

[0088] The results clearly indicated that 300 mg/kg of GVG blocked theexpression of heroin-induced CPP.

[0089] Therefore, the results of Table 1 and Table 2 taken togetherdemonstrated that GVG was able to block the craving for heroin, apowerfully addictive analgesic, while not decreasing analgesiceffectiveness on reducing pain. Thus, a GABAergic agent, such as GVGused in combination with opioid analgesics will decrease the likelihoodof addiction to the analgesic without decreasing their therapeuticeffects in pain management.

[0090] While there have been described what are presently believed to bethe preferred embodiments of the present invention, those skilled in theart will realize that other and further embodiments can be made withoutdeparting from the spirit of the invention, and it is intended toinclude all such further modifications and changes as come within thetrue scope of the claims set forth herein.

1. A composition for treating pain in a mammal comprising: a) apharmaceutically acceptable analgesic which has addictive liability, andb) a GABAergic agent which is effective in reducing or eliminating saidaddictive liability without interfering with the pain relievingproperties of said analgesic.
 2. A composition as described in claim 1wherein said analgesic is a narcotic analgesic.
 3. A composition asdescribed in claim 1 wherein said analgesic is selected from the groupconsisting of alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations.
 4. A composition as described in claim 3 wherein saidanalgesic is morphine.
 5. A composition as described in claim 1 whereinsaid GABAergic agent is selected from the group consisting of gammavinyl GABA (GVG), gabapentin, valproic acid, progabide,gamma-hydroxybutyric acid, fengabine, cetylGABA, topiramate, tiagabine,acamprosate (homo-calcium-acetyltaurine),pharmaceutically acceptablesalts thereof, enantiomers or a racemic mixture thereof, or anycombinations thereof.
 6. A composition as described in claim 5 whereinsaid GABAergic agent is GVG.
 7. A composition as described in claim 5wherein said GABAergic agent is topiramate.
 8. A composition asdescribed in claim 1 wherein said analgesic is present in an amount ofabout 5 μg to about 1000 mg.
 9. A composition as described in claim 1wherein said analgesic is present in an amount of about 50 μg to about100 mg.
 10. A composition as described in claim 1 wherein said GABAergicagent is present in an amount of about 0.5 to about 5.0 grams.
 11. Acomposition as described in claim 1 wherein said addictive liabilitycomprises development of dependency.
 12. A composition as described inclaim 1 wherein said addictive liability comprises development oftolerance for said analgesic.
 13. A composition for treating pain in amammal comprising: a) the analgesic morphine, which has addictiveliability, and b) the GABAergic agent GVG which is effective in reducingor eliminating said addictive liability without interfering with theanalgesic properties of morphine.
 14. A composition for treating pain ina mammal comprising: a) the analgesic morphine, which has addictiveliability, and b) the GABAergic agent topiramate which is effective inreducing or eliminating said addictive liability without interferingwith the analgesic properties of morphine.